Dipeptidylpeptidase IV (EC3.4.14.5, referred to as “DPP-IV” or “CD26,” hereinafter) is a serine protease that specifically hydrolyzes polypeptides having proline or alanine at position 2 on the C-terminal side of these amino acid residues, cleaving dipeptides Xaa-Pro or Xaa-Ala from the N-terminus of the polypeptides (Xaa may be any amino acid).
One biological function of DPP-IV is the inactivation of glucagon-like peptide 1 (GLP-1) by cleaving the N-terminal His-Ala dipeptide of GLP-1 (Non-Patent Document 1). The GLP-1 inactivated by DPP-IV is thought to act as an antagonist on GLP-1 receptors, further decreasing the physiological activity of GLP-1 (Non-Patent Document 2). GLP-1, a peptide hormone secreted from endocrine L-cells found primarily in intestinal epithelium, is known to act on β-cells of the pancreatic Langerhans' islets in a glucose-dependent manner to promote the insulin secretion, thus decreasing the blood glucose level (Non-Patent Documents 3 and 4). Having an ability to promote insulin biosynthesis and β-cell growth, GLP-1 is an essential factor for the maintenance of β-cells (Non-Patent Documents 5 and 6). It has been reported that GLP-1 also acts to promote glucose utilization by peripheral tissue and, when intraventricularly administered, decreases food intake and motility of GI tract (Non-Patent Documents 7 through 10).
A DDP-IV inhibitor is believed to increase the GLP-1 activity by suppressing the decomposition of innate GLP-1. The increased GLP-1 activity stimulates insulin secretion and improves glucose metabolism. For this reason, DPP-IV inhibitors are expected to be useful in the prevention and/or treatment of diabetes, in particular type II diabetes (Non-Patent Documents 11 and 12). The compounds are expected to be also effective in the prevention and/or treatment of other diseases that are caused or worsened by decreased glucose metabolism (for example, diabetic complications, hyperinsulinemia, hyperglycemia, abnormal lipid metabolism and obesity).
The roles of DPP-IV in a living body other than the inactivation of GLP-1 and how the enzyme is involved in the onset of various diseases have been described in many reports as described below.
(a) DPP-IV inhibitors and their antibodies prevent the invasion of HIV into cells. Expression of CD26 is reduced in T-cells derived from patients infected with HIV-1 (Non-Patent Document 13). HIV-1 Tat protein binds to DPP-IV (Non-Patent Document 14).
(b) DPP-IV is involved in immune responses. DPP-IV inhibitors and their antibodies suppress the growth of T-cells stimulated by antigens (Non-Patent Document 15). T-cells stimulated by antigens express an increased level of DDP-IV (Non-Patent Document 16). DDP-IV is involved in the cytokine production and other functions of T-cells (Non-Patent Document 17). DDP-IV binds to adenosine deaminase (ADA) on the T-cell surface (Non-Patent Document 18).
(c) Expression of DPP-IV is increased in the skin fibroblasts of patients with rheumatoid arthritis, psoriasis, and lichen planus (Non-Patent Document 19).
(d) High DPP-IV activity is observed in patients with benign prostatic hypertrophy and in the homogenate of the prostatic tissue (Non-Patent Document 20). DPP-IV in the lung endothelium acts as an adhesive molecule for lung-metastatic breast cancer and prostatic cancer in rats (Non-Patent Document 21).
(e) The DPP-IV defective variant of F344 rats has lower blood pressure than the wild-type F344 rats. DPP-IV interacts with a protein that plays a crucial role in sodium reabsorption by the kidney (Patent Documents 1 and 2).
(f) The inhibition of DPP-IV activity offers an effective approach to the prevention and/or treatment of myelosuppressive diseases, while DPP-IV-activating agents are expected to serve as drugs to increase the white blood cell count and/or treat infectious diseases (Patent Document 3).
These observations indicate that DPP-IV inhibitors can be useful in the prevention and/or treatment of diabetes (in particular, type II diabetes) and/or diseases other than diabetic complications that involve DPP-IV. For example, DPP-IV inhibitors are expected to be useful in the prevention and/or treatment of AIDS following infection with HIV, rejection following organ/tissue transplantation, multiple sclerosis, rheumatoid arthritis, inflammation, allergies, osteoporosis, psoriasis and lichen planus, benign prostatic hypertrophy, lung metastasis of breast and prostatic cancers, hypertension and infectious diseases. DPP-IV inhibitors are also expected to be used to facilitate diuresis, decrease myelosuppression and increase white blood cell count.
Among existing DPP-IV inhibitors are pyrrolidine derivatives described in Patent Documents 4 through 11, heterocyclic derivatives described in Patent Documents 12 and 13, and β-amino acid derivatives described in Patent Documents 14 and 15.
Patent Document 16, a US patent, discloses a single bicycle[2.2.2]octane derivative that inhibits DPP-IV activity. This compound, however, is completely different from the compounds of the present invention in its structure and mechanism for DPP-IV inhibition. Patent Document 17 mentions a bicycle derivative structurally similar to the compounds of the present invention. However, there is no description in this literature concerning any of the compounds of the present invention, nor have any examples been presented of the compounds.
None of the previously described DDP-IV inhibitors are practical enough in terms of DDP-IV inhibitory activity, selectivity for DPP-IV, stability, toxicity and biological kinetics. Thus, a constant need exists for effective DDP-IV inhibitors.    [Non-Patent Document 1] American Journal of Physiology, Vol. 271 (1996): ppE458-E464.    [Non-Patent Document 2] European Journal of Pharmacology, Vol. 318 (1996): pp 429-435    [Non-Patent Document 3] European Journal Clinical Investigation, Vol. 22 (1992): p154    [Non-Patent Document 4] Lancet, Vol. 2 (1987): p1300    [Non-Patent Document 5] Endocrinology, Vol. 42 (1992): p856    [Non-Patent Document 6] Diabetologia, Vol. 42 (1999): p 856    [Non-Patent Document 7] Endocrinology, Vol. 135 (1994): p2070    [Non-Patent Document 8] Diabetologia, Vol. 37 (1994): p1163    [Non-Patent Document 9] Digestion, Vol. 54 (1993): p392    [Non-Patent Document 10] Dig. Dis. Sci., Vol. 43 (1998): p1113    [Non-Patent Document 11] Diabetes, Vol. 47 (1998): pp1663-1670    [Non-Patent Document 12] Diabetologia, Vol. 42 (1999): pp1324-1331    [Non-Patent Document 13] Journal of Immunology, Vol. 149 (1992): p3037    [Non-Patent Document 14] Journal of Immunology, Vol. 150 (1993): p2544    [Non-Patent Document 15] Biological Chemistry (1991): p305    [Non-Patent Document 16] Scandinavian Journal of Immunology, Vol. 33 (1991): p737    [Non-Patent Document 17] Scandinavian Journal of Immunology, Vol. 29 (1989): p127    [Non-Patent Document 18] Science, Vol. 261 (1993): p466    [Non-Patent Document 19] Journal of Cellular Physiology, Vol. 151 (1992): p378    [Non-Patent Document 20] European Journal of Clinical Chemistry and Clinical Biochemistry, Vol. 30 (1992): p333    [Non-Patent Document 21] Journal of Cellular Physiology, Vol. 121 (1993): p1423
[Patent Document 1]WO 03/015775 Pamphlet[Patent Document 2]WO 03/017936 Pamphlet[Patent Document 3]WO 03/080633 Pamphlet[Patent Document 4]WO 95/15309 Pamphlet[Patent Document 5]WO 98/19998 Pamphlet[Patent Document 6]WO 00/34241 Pamphlet[Patent Document 7]WO 02/14271 Pamphlet[Patent Document 8]WO 02/30890 Pamphlet[Patent Document 9]WO 02/38541 Pamphlet[Patent Document 10]WO 03/002553 Pamphlet[Patent Document 11]US 02/0193390 Publication[Patent Document 12]WO 02/062764 Pamphlet[Patent Document 13]WO 03/004496 Pamphlet[Patent Document 14]WO 03/000180 Pamphlet[Patent Document 15]WO 03/004498 Pamphlet[Patent Document 16]US 02/0193390 Publication[Patent Document 17]WO 02/38541 Pamphlet